1. Rhinitis
Rhinitis refers to what is known as an inflammation of the so-called nasal mucous membrane, and histopathologically it is an exudative inflammation, often exhibited as pyogenic inflammation and allergic inflammation. In any cases, it is characterized by exudation of fluid components from the blood vessels, edema, cellular exudates and supersecretion.
Rhinitis includes various types such as acute rhinitis (so-called cold in the nose), chronic rhinitis, and allergic rhinitis depending on the cause and symptoms; usually, it is classified into four types depending on their causes and symptoms, namely infectious rhinitis, hypersensitive non-infectious rhinitis, irritant rhinitis, and others, as shown below.
TABLE 11. Infectious(a) Acute rhinitis(b) Chronic rhinitis2. Hyper-(a) Combined type(i) AllergicPerennial allergicsensitive(hypersensitiverhinitisnon-infectiousnose)Seasonal allergicrhinitis(ii)Vasomotor rhinitisNon-allergic(idiopathicrhinitis)Non-allergicrhinitis witheosinophiliasyndrome(b) Rhinorrhea typeGustatory rhinitisCold airinhalation-inducedrhinitisSenile rhinitis(c) Congestive typeDrug-inducedrhinitisPsychogenic rhinitisPregnancy rhinitisEndocrine rhinitisCold-inducedrhinitis(d) Dry type3. Irritant(a) Physical irritant-induced rhinitis(b) Chemical irritant-induced rhinitis(c) Radiation-induced rhinitis4. Others(a) Atrophic rhinitis(b) Specific granulomatous rhinitis
Hereinafter, rhinitis of these types is explained.
Infectious rhinitis is classified into acute rhinitis (the so-called cold in the nose) which progresses within a short period, and chronic rhinitis which persists for a long period. Infective chronic paranasal sinusitis, in which nasal cavities mainly around the ethmoid sinus and middle nasal meatus are affected, is also included in the infectious rhinitis.
Of the infectious rhinitis, most cases of the acute rhinitis are classified as a cold in the nose induced by infections mainly viral, but there are also many cases of acute simple rhinitis.
Symptoms of acute viral rhinitis (the cold) are characterized by runny nose, stuffy nose, and postnasal rhinorrhea in which nasal drip flows into the throat, coughing, slight fever and others. To relieve stuffy nose, vasoconstrictive agents such as spray-type nasal drop preparations of phenylephrine and oral medicines of pseudoephedrin are used. However, the use of such spray preparations must be limited to 3 to 4 days. When used for a longer period than this, the effectiveness of the medicine is reduced and a rebound phenomenon, in which the nasal mucous membranes become more congested than prior to the use, occurs. In addition, while antihistamine drugs have an effect to suppress runny nose, they also have side effects such as drowsiness.
In contrast, contributing factors of acute simple rhinitis include sinusitis, tonsillitis, and inflammation of adjacent organs such as the adenoids, as well as dust, soot, tobacco, air pollution, extreme temperature change, excessive dryness and moistness. Symptoms initiate with sneezing, and include excess rhinorrhea (nasal drip), nasal occlusion (stuffy nose), and impairment of the sense of smell; they resemble the symptoms of a cold of the nose, but do not include systemic symptoms such as fever. The nasal mucous membrane congests and swells. Disease is usually cured within 10 days, but occasionally bacterial infection occurs, worsening the symptoms and causing a fever. A prolonged course of the disease results in sinusitis or chronic rhinitis. For treatment, patients are rested and kept warm, and supportive measures are also taken, such as the use of antifebriles, analgesics, antitussive agents, and anti-inflammatory agents; when a bacterial infection occurs, antibiotics are used.
Chronic rhinitis is a long-term infectious rhinitis; when contributing factors of acute rhinitis are not improved, acute rhinitis turns into chronic rhinitis. Chronic rhinitis is often associated with chronic sinusitis. Chronic rhinitis has three pathological conditions, each referred to as chronic simple rhinitis, chronic hypertrophic rhinitis, and atrophic rhinitis.
Chronic simple rhinitis is a pathological condition in which the mucous membrane of the nasal cavities swells chronically due to repeated acute rhinitis. Symptoms of chronic simple rhinitis are mostly identical to those of hypertrophic rhinitis, and include nasal occlusion, excess rhinorrhea, impairment of the sense of smell and headache. However, it differs from chronic hypertrophic rhinitis in that swelling of the nasal mucous membrane is improved by vasoconstrictive agents. For treatment, removal of contributing factors is most important; conservative management such as the application of drugs and use of anti-inflammatory agents is also carried out.
Chronic hypertrophic rhinitis is caused by severe long-lasting inflammation. Chronic hypertrophic rhinitis is the most prevalent pathological condition among the chronic rhinitides, and exhibits severe swelling and thickening of the nasal mucous membrane.
Chronic atrophic rhinitis refers to a pathological condition wherein the mucous membrane of the nasal cavities and the bone tissues of the nose become atrophied, resulting in widened nasal cavities. Stuffy nose occurs on both sides and purulent nose drips are discharged. Discharges inside the nose attach to the wall of the nasal cavity in a crust like manner, releasing a bad odor.
Hypersensitive non-infectious rhinitis is a rhinitis wherein inflammation is caused by the mucous membrane of the nasal cavities that have become hypersensitive due to diathesis and some other reasons, so that it occurs by stimulations other than viruses and bacterial infection.
Furthermore, hypersensitive non-infectious rhinitis can be classified into combined-type rhinitis (hypersensitive nose), rhinorrhea-type rhinitis, congestive-type rhinitis, and dry-type rhinitis. In addition, combined-type rhinitis (hypersensitive nose) is further classified into allergic rhinitis and non-allergic rhinitis. Furthermore, allergic rhinitis can be classified into, from their favored onset timing, perennial allergic rhinitis and seasonal allergic rhinitis, and non-allergic rhinitis can be classified into vasomotor rhinitis (idiopathic rhinitis) and non-allergic rhinitis with eosinophilia syndrome. In addition, rhinorrhea-type rhinitis can be classified into gustatory rhinitis, cold air inhalation-induced rhinitis, and senile rhinitis; and congestive-type rhinitis can be classified into drug-induced rhinitis, psychogenic rhinitis, pregnancy rhinitis, and cold-induced rhinitis.
Combined-type rhinitis (hypersensitive nose) usually accompanies some of the symptoms including sneezing, watery rhinorrhea, and nasal occlusion (stuffy nose); for example, sneezing with watery rhinorrhea, sneezing with watery rhinorrhea and nasal occlusion.
Of the combined-type rhinitides (hypersensitive nose), allergic rhinitis is induced by the immune response of the body against causative substances in the external environment. Causative substances of allergic rhinitis generally include house dust, house dust mites, fungi, pollens, grasses, trees, and animals. More specifically, allergic rhinitis is a type-I allergic disease of the nasal mucous membrane, and is characterized by, in principle, paroxysmal repetitive sneezing, watery rhinorrhea, and nasal occlusion. Since allergic rhinitis is a type-I allergic disease, patients often have an allergic disposition (past history, complication, and family history of allergy), and are characterized by an increased serum level of specific IgE antibodies, increases in the local mast cells as well as local and blood eosinophils, and enhancement of non-specific sensitivity of the mucous membrane.
Of the allergic rhinitides, perennial allergic rhinitis is mostly caused by house dust and house dust mites, and seasonal allergic rhinitis is mostly caused by pollen.
Of the non-allergic rhinitides, vasomotor rhinitis (idiopathic rhinitis) is a kind of chronic rhinitis with some symptoms similar to those of general allergic rhinitis, i.e., nasal occlusion (stuffy nose), sneezing, and watery rhinorrhea (runny nose), but showing no apparent antigens. Symptoms include, in addition to stuffy nose, swelling of the mucous membrane with various colors from red to violet. Sometimes mild inflammation is observed in the paranasal sinuses. For treatment, anti-histamine drugs and anti-allergy agents are used.
Of the non-allergic rhinitides, non-allergic rhinitis with eosinophilia syndrome refers to a disease wherein an allergy test result is negative, but the amount of eosinophils in the nasal drip alone increases to some extent.
The rhinorrhea-type hypersensitive non-infectious rhinitis is characterized by rhinorrhea, and there are three types: gustatory rhinitis, cold air inhalation-induced rhinitis, and senile rhinitis. Gustatory rhinitis often occurs during eating highly-irritating foods or very hot foods. Cold air inhalation-induced rhinitis is a rhinorrhea induced by inhalation of cold air, which is famous as the skier's nose. Senile rhinitis is also characterized by watery rhinorrhea, but its cause is unknown.
Of the hypersensitive non-infectious rhinitides, congestive rhinitis is characterized by nasal occlusion as a predominant symptom, and is further classified into drug-induced rhinitis, psychogenic rhinitis, pregnancy rhinitis, endocrine rhinitis, and cold-induced rhinitis. Any of these types of rhinitis is characterized by congestion of the mucous membrane, and a stuffy nose is often observed.
Among them, drug-induced rhinitis is characterized by stuffy nose as a predominant symptom, which is reportedly possibly induced as a side effect of long-term continuous administration of drugs such as sympatholytic antihypertensive drugs, vasodilatory antihypertensive drugs, □-stimulation antihypertensive drugs, bronchodilators, anti-depressants, and contraceptive pills. However, the most frequently observed cause is the abuse of a vasoconstrictor nasal drop preparation against nasal occlusion. Psychogenic rhinitis is observed with chronic stress, depression, and neurosis, and is characterized by nasal occlusion. Pregnancy rhinitis occurs in the second trimester or later of pregnancy, and its onset is considered to be particularly associated with actions of female hormone, especially estrogen, on the blood vessels of nasal mucous membranes and on autonomic receptors. Endocrine rhinitis is known with emphasis on a decrease in thyroid activity. But the number of the case is small. Cold-induced rhinitis is considered to be induced by reflex vasodilation in nasal mucosa, via cold stimulation of the body, in particular the hands and feet.
Of the hypersensitive non-infectious rhinitides, dry-type rhinitis (dry nose) is presumed to be induced as follows: when the humidity in a room becomes 20% or lower due to dry air and heating in winter, symptoms such as dry mucous membrane, crusting, and nasal bleeding occur, and hypersensitivity to irritation increases due to drying of the mucous layer, leading to nasal dryness and nasal occlusion sensations.
Irritant rhinitis is often caused by the working environment of an occupation, and is classified into physical irritant-induced rhinitis, chemical irritant-induced rhinitis and radiation-induced rhinitis based on the cause. Such physical irritant-induced rhinitis and chemical irritant-induced rhinitis develop by physical or chemical, acute or chronic irritation of mucous membranes. Inflammation is sometimes caused by radiation of nasal mucous membranes, which is called radiation-induced rhinitis.
Other types of rhinitis include atrophic rhinitis and specific granulomatous rhinitis. As symptoms of atrophic rhinitis (ozena), the nasal mucous membrane becomes thin and hard, and the nasal cavities extend to induce dryness; however, this type of rhinitis is currently rare in Japan. Specific granulomatous rhinitis is a rhinitis associated with granuloma, and includes specific rhinitis (tuberculosis, syphilis, etc.), sarcoidosis, and Wegener granulomatosis; however, the number of cases is extremely small.
In any case, rhinitis is a state of the nasal mucous membrane that is swelling by inflammation, characterized by symptoms such as runny nose and stuffy nose, which disturbs the daily lives of patients who experience difficulty in breathing; thus, rhinitis is a troublesome disease.
2. Treatment of Rhinitis
In the treatment of rhinitis, in particular allergic rhinitis, methods are generally selected based on the combination of severity level and disease type. The selection is not standardized, but according to “Guidelines for medical care of nasal allergies, 2009 edition” (edited by the committee for creation of guidelines for medical care of nasal allergies) treatment methods are as follows.
For mild cases, the first choice should be second-generation antihistamine drugs or chemical mediator releasing suppressants. When side effects such as drowsiness and drymouth are not observed, first-generation antihistamine drugs having a fast-acting property may be administered.
In moderate cases, for sneezing/rhinorrhea type, one of the following:
(1) second-generation antihistamine drugs,
(2) chemical mediator releasing suppressants, or
(3) steroid nasal sprays,
is selected, and if necessary, either (1) or (2) is combined with (3).
In moderate cases, for nasal-occlusion type or mixed type with particularly severe nasal-occlusion cases, one of the following:
(1) anti-leukotriene drugs,
(2) anti-prostaglandin D2/thromboxane A2 drugs, or
(3) steroid nasal sprays,
is selected, and if necessary, either (1) or (2) is combined with (3).
In severe cases, when sneezing and rhinorrhea are particularly severe, a second-generation antihistamine drug is combined with a steroid nasal spray. Meanwhile, among severe cases of nasal-occlusion type or mixed type wherein nasal occlusion is particularly severe, an anti-leukotriene drug or anti-prostaglandin D2/thromboxane A2 drug is combined with a steroid nasal spray.
Attempts to remove and avoid antigens are required in any case; when sequential therapy is possible, application of specific immunotherapy is a choice, with which long-term remission can be expected. In cases of apparent morphological defects such as deviation of the nasal septum, or in cases wherein effects of drug therapy on nasal occlusion are insufficient, operative therapy is one choice of treatment. Effectiveness of antihistamine nasal sprays has been reported, but they are considered to be inferior to steroid nasal sprays.
As described above, representative treatments of allergic rhinitis include removal and avoidance of allergens, drug therapy, specific immunotherapy, and operative therapy; drugs used in the drug therapy can be classified into the following drug groups based on their action mechanism: steroids, histamine receptor antagonists, chemical mediator releasing suppressants, thromboxane A2 receptor antagonists, thromboxane A2 synthesis inhibitors, leukotriene antagonists, and Th2 cytokine inhibitors.
Among them, examples of steroids include beclomethasone (brand name: Beconase, Aldecin, Rhinocort, Salcoat), fluticasone (brand name: Flixonase), etc. Examples of histamine receptor antagonists include ketotifen (brand name: Zaditen), mequitazine (brand name: Zesulan), fexofenadine (brand name: Allegra), ebastine (brand name: Ebastel), bepotastine (brand name: Talion), olopatadine (brand name: Allelock), loratadine (brand name: Claritin), etc. Examples of chemical mediator releasing suppressants include cromolyn (brand name: Intal) and tranilast (brand name: Rizaben), etc. Examples of thromboxane A2 receptor antagonists include seratrodast (brand name: Bronica) and ramatroban (band name: Bynas), etc. Examples of thromboxane A2 synthesis inhibitors include ozagrel (brand name: Domenan or brand name: Vega), etc. Examples of leukotriene antagonists include montelukast (brand name: Singulair, Kipres) and pranlukast (brand name: Onon), etc. Examples of Th2 cytokine inhibitors include suplatast (brand name: IPD), etc.
Thus, while there are a number of drugs usable as therapeutic preparations for allergic rhinitis, steroids or histamine receptor antagonists are frequently used for moderate cases, and a combination of steroids and histamine receptor antagonists is used for severe cases.
Meanwhile, steroid nasal sprays elicit some local side effects such as nasal irritation, dryness, burning sensation of the nose, and nasal bleeding. In addition, when steroids are used for a long time, caution should be taken to avoid steroid withdrawal difficulty, and complications of infection should be a concern. There are a considerable number of cases of rhinitis that show resistance to steroid therapy. Furthermore, steroid nasal sprays do not have a long duration of effectiveness, and in the case of adult patients, application of about 4 times a day is necessary. Accordingly, many patients hesitate to use steroid nasal sprays, and there is a report stating that more than half of the patients did not take drugs in accordance with their prescription.
Furthermore, while antihistamine drugs suppress allergic reactions and their symptoms, they have disadvantages that they cause dryness in the nasal mucous membrane and drowsiness. In addition, while injection of allergens (hyposensitization therapy) leads to a long-term immunological tolerance against a specific causative substance, it takes from several months to several years for the manifestation of sufficient effects.
Under such circumstances, development of a novel therapeutic preparation for rhinitis that is not only efficacious and safe for patients with rhinitis, in particular patients with allergic rhinitis, but also has fewer local side effects without complication of infections, has been awaited. Moreover, development of a therapeutic preparation for rhinitis that is also efficacious for patients with severe cases who show treatment resistance to steroids has been awaited.
3. Natriuretic Peptides:
There are three known families of natriuretic peptides (NPs), named atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP); their well-known members are composed of 28, 32, and 22 amino acid residues, respectively.
(1) ANP and BNP:
ANP and BNP are synthesized mainly by the atria and the ventricles, respectively, and released from the heart into the whole body. It is thought that nearly 100% of the circulating ANP and BNP in the blood originate from the heart. These ANP and BNP are reported to be deeply involved in a numerous diseases, including hypertension, cardiomegaly, cardiac failure, myocardial infarction, valvular heart disease, cardiac dysrhythmia, and pulmonary hypertension.
Human ANP is a peptide produced and released by atrial cardiocytes, and is composed of 28 amino acids, of which the 7th cysteine and the 23rd cysteine are bonded by a disulfide bond to form a ring structure. ANP has been shown to have diuretic effects in the kidneys and relaxes/dilates vascular smooth muscle cells in the blood vessels. In contrast, human BNP is a peptide produced and released by ventricular cells, and is composed of 32 amino acids, of which the 10th cysteine and the 26th cysteine are bonded by a disulfide bond to form a ring structure. BNP also possesses both diuretic and vasodilating effects. BNP was originally isolated and identified in the porcine brain in Japan in 1988, and is also called brain natriuretic peptide.
Both ANP and BNP bind to the receptor NPR-A (also called GC-A) having a guanylate cyclase domain, and exert their effects as stated above by stimulating the production of cGMP. In fact, secretion of ANP is stimulated in response to an increase in the atrial pressure by its distension in congestive heart failure, etc., and through its action as stated above, ANP relieves the symptoms of congestive heart failure, etc. Likewise, BNP's release is stimulated during certain conditions including myocardial infarction, and BNP, through its action as described above, relieves the symptoms associated with myocardial infarction, etc. (Refer to non-patent literature 1). Although most of the circulating BNP derives from the ventricles, some BNP is released by the atria. In cardiac failure, the level of expression of both ANP and BNP increases to as much as 100 times more the normal level, but the increase of BNP expression is reported to be both greater and faster than that of ANP. While ANP (hANP) is marketed as a prescription drug for treating acute cardiac failure in Japan, BNP is clinically used in the United States.
(2) CNP:
CNP, which was once thought to function only as a brain peptide because it was first found in the brain, has now been clarified to exist in the periphery as well. In the vascular walls, in particular, CNP specific receptors were found to be abundant in the smooth muscle cells, and CNP to be produced by the cells of the monocyte/macrophage linage and the endothelial cells. For those reasons, CNP is speculated to function in the vascular walls as a local mediator involved in inhibition of growth of vascular smooth muscle cells. Its clinical application is currently being investigated for possible prevention of restenosis by CNP administration, which occurs with a certain frequency after percutaneous transluminal coronary angioplasty (PTCA) performed on patients with ischemic heart failure.
Recently it has been reported that intravenous administration of CNP remarkably improves cardiomegaly and fibrosis associated with myocardial infarction, and improves cardiac functions in animal experiments. Cardiac fibrosis is known to cause diastolic ventricular failure and cardiac dysrhythmia. Since CNP possesses a powerful action to suppress fibroblast proliferation, the potential of CNP as an anti-fibrotic medication for the heart is under investigation. Since CNP is a hormone occurring naturally in the body, there is little concern of adverse side effects; accordingly clinical application of CNP as a therapeutic preparation for arteriosclerotic diseases and heart diseases is expected. Here, examples of CNP include CNP-22 composed of 22 amino acids, and CNP-53 wherein 31 amino acid residues are attached to the N-terminal of CNP-22.
(3) Natriuretic Peptide Receptors:
Natriuretic peptide receptors are classified into three subtypes; NPR-A receptor (also called GC-A) and NPR-B receptor (also called GC-B) both of which contain a guanylate cyclase domain, and NPR-C receptor which lacks a guanylate cyclase domain. It is known that ANP can bind to NPR-A and NPR-C receptors, BNP can bind to NPR-A and NPR-C receptors, and CNP can bind to NPR-B and NPR-C receptors.
The activation of NPR-A receptors is suggested to induce vasodilation, a diuretic effect, and inhibition of cell growth, while NPR-B receptors are abundant in vascular smooth muscle cells and thought to be involved in the growth inhibition of vascular smooth muscle cells.
(4) Relationship Between Natriuretic Peptides and the Immune System:
Historically, natriuretic peptides were first discovered as a peptide released from the atria, later named ANP, and its vasodilating and diuretic actions gathered attention. BNP and CNP were then discovered as peptides similar to ANP. This historical background offers an explanation as to why any attention to the relationship between natriuretic peptides and the immune system have been focused on those related to the cardiovascular system. CNP knock-out mice demonstrated impaired growth of cartilage resulting in a dwarfism-like phenotype (refer to Non-patent literature 2), which directed some interest to the relationship between arthritis and natriuretic peptides.
ANP is implicated in playing a role in arthritis and sepsis as it inhibits the release of inflammatory cytokines including tumor necrosis factor (TNF-α) and interleukin 1β (IL-1β) by macrophages (refer to Non-patent literature 3). This literature, however, does not mention ANP's relationship with rhinitis.
Similarly, the blood concentration of BNP has been reported to increase with the rejection response following heart transplant, and therefore it is suggested that it is associated with immune regulation in the cardiovascular system (refer to Non-patent literature 4). However, this literature does not describe any connection between BNP and rhinitis.
Taking into account the observation that there is an increase in the blood concentration of BNP during the heart graft rejection, Kuroski de Bold et al. have investigated the immunoregulatory action of natriuretic peptides, and have demonstrated that both ANP and BNP inhibit the lymphocyte growth (refer to Non-patent literature 5). However, there is no connection between natriuretic peptides and rhinitis mentioned in this literature.
Chiurchiu et al. on the other hand have investigated the immunoregulatory actions of BNP focusing on its association with heart disease and sepsis, and showed that BNP promotes the release by macrophages of pro-inflammatory cytokines such as arachidonic acid, prostaglandin E2 (PGE2), and leukotriene B4 (LTB4), and also promotes the release of anti-inflammatory cytokines including interleukin 10 (IL10). Thus, while BNP is indicated to have some action in the regulation of inflammatory responses, whether BNP acts overall to suppress or promote inflammatory responses remains inconclusive in the literature (refer to Non-patent literature 6). This literature also does not mention any connection between BNP and rhinitis.
Similarly, CNP is reported to be released by macrophages (refer to Non-patent literature 7), and while investigating the roles of CNP in cardiac ischemia and myocardial damage after reperfusion, Scotland et al. report that CNP suppresses platelet aggregation and lymphocyte migration (refer to Non-patent literature 8). The connection between CNP and rhinitis, however, is not described in these literatures.
Likewise, Obata et al. examined the roles played by CNP in myocarditis using a rat myocarditis model generated by injecting pig myosin. They reported that continuous administration of CNP for 1 week to the model suppressed necrosis and inflammation of the cardiac tissues, while at the same time promoted the regeneration of blood vessels, thereby preventing functional loss of the heart (refer to Non-patent literature 9). Nevertheless, there is no mention in this literature to suggest a connection between CNP and rhinitis.
In addition, based on the observation that CNP knock-out mice show a dwarfism-like phenotype, attention has been paid to the potential connection between CNP and cartilage growth. Agoston et al. demonstrated that when incubated with Dexamethasone, the primary-cultured chondrocytes extracted from the tibial bones of mouse embryos had significantly increased the expression of CNP genes (refer to Non-patent literature 10). This literature, however does not describe any connections between CNP and rhinitis.
It is evident that the connections between natriuretic peptides and the immune system have drawn increasing attention in recently years, but it is limited only to the inflammation of the cardiovascular system and arthritis, and the relationship between rhinitis and natriuretic peptides have never been reported.
(5) Reports on the Application of Natriuretic Peptides:
Following are some examples of a number of applications of CNP, BNP and ANP.
Toshiko Koide and her colleagues have proposed a preparation for repair/regeneration of tissues and organs, comprising a composition that comprises any of ANP, BNP, CNP, urodilatin (P-Uro), precursors thereof, derivatives thereof, or combinations thereof as an active ingredient, and that may comprise pharmaceutically commonly-used diluents, excipients, fillers, and auxiliary agents (refer to Patent Literature 1).
However, specific examples of repair and regeneration of tissues and organs relate only to the regeneration of myocardiocytes, hypodermal tissue, hair, and improvement of cracked, rough skin due to wet works; they all correspond to ANP administration. There is no statement that implies therapeutic preparations for treating rhinitis by means of administration of CNP or BNP.
Masaharu Tanaka and his colleagues have proposed a C-type natriuretic peptide exhibiting a growth inhibitory action of vascular smooth muscle cells, as well as a growth inhibitory preparation of vascular smooth muscle cells containing such peptide as its active ingredient (refer to Patent Literature 2).
This, however, relates to the use of CNP in a growth inhibitory agent of vascular smooth muscle cells but does not imply application of CNP or BNP to therapeutic preparations for rhinitis.
Katsuhiko Nakada and his colleagues proposed an eye drop for promoting lacrimal secretion or for treating keratoconjunctival disorder, containing as its active ingredient a natriuretic peptide, and they listed ANP, BNP and CNP as examples of usable natriuretic peptides (refer to Patent Literature 3).
This, however, only relates to the application of the property of ANP, CNP and BNP to promote lacrimal secretion in an eye drop for treating keratoconjunctival disorder, and does not indicate the use of CNP or BNP in a therapeutic preparation to treat rhinitis.
Kazuwa Nakao and his colleagues proposed a composition for increasing the body height containing a guanyl cyclase B (GC-B) activator as the active ingredient, which is to be administered to an individual without FGFR3 abnormality (refer to Patent Literature 4).
This indicates an application of CNP in a composition for increasing the body height based on the finding that the nose-anus length in the transgenic mice overexpressing CNP was larger than that in normal litters, but dose not imply the use of CNP or BNP in a therapeutic preparation for rhinitis.
Kazuwa Nakao and his colleagues also proposed a prophylactic agent or therapeutic preparation for the inflammation of the joints containing a guanyl cyclase B (GC-B) activator such as CNP as an active ingredient (refer to Patent Literature 5).
However, this relates only to the application of CNP in a therapeutic preparation or prophylactic preparation for inflammation of the joints based on the study revealing that, compared to their litter mates, the articular cartilages grow thicker in the transgenic mice overexpressing CNP, along with the observation that the arthritis is repressed by the continuous administration of CNP to model animals of arthritis. Hence this does not imply the application of CNP or BNP in a therapeutic preparation for rhinitis.
In addition, Masaharu Tanaka and his colleagues reported that CNP differs from ANP and BNP in the structure, function and effects as stated below (refer to Patent Literature 2).
“At present, both ANP and BNP are thought to act as a hormone secreted by the heart into the blood, as well as a neurotransmitter, and to play an important role in maintaining the amount of body fluid and homeostasis of blood pressure . . . . There are many unknown points in the physiological role of CNP as a natriuretic peptide. Namely, since CNP has a primary amino acid sequence similar to that of ANP and BNP and shows a natriuretic action and a hypotensive action upon in vitro administration, CNP was relegated to the natriuretic peptide family. However, because the natriuretic action and hypotensive action of CNP are significantly weaker than those of ANP and BNP (from 1/50 to 1/100), . . . CNP has held a unique position in the natriuretic peptide family, and has been presumed to be playing a role different from the maintenance of amounts of body fluid and homeostasis of blood pressure . . . . Comparing the structure of CNP with that of ANP/BNP, CNP differs from ANP or BNP in the following points . . . . Namely, the primary amino acid sequence of CNP completely differs from that of ANP or BNP at the exocyclic N-terminal domain; of the 17 amino acid residues in the endocyclic domain, 5 residues and 4 residues in CNP differ from those in ANP and BNP, respectively. In addition, the structure of the exocyclic C-terminal domain of CNP largely differs from that of ANP or BNP, and CNP does not have a tail structure existing in ANP or BNP (in the case of ANP and BNP, 5 amino acid residues and 6 amino acid resides, respectively, are attached to the C-terminal of the cyclic structure in ANP and BNP; this structure is called a tail structure for descriptive purposes). Thus-described structural differences between CNP and ANP/BNP are clearly involved in the manifestation of the above-mentioned characteristic pharmacological effects of CNP.”